In recent years, patients of metabolic syndrome have increased rapidly especially in advanced countries. Metabolic syndrome is a compound lifestyle disease where visceral fat type obesity (visceral obesity, abdominal obesity), and two or more of hyperglycemia, hypertension, and hyperlipidemia are combined. In accordance with such compound symptoms, a metabolic syndrome can accelerate the progression of heart disease, cerebral stroke or the like, and are the greatest cause of notable deterioration of the healthy lifespan and quality of life of the elderly. Under these circumstances, in order to maintain the vitality of society as a whole and reduce healthcare costs, there is a great social need for overcoming metabolic syndrome.
As an important molecular basis linking metabolic syndrome with arteriosclerosis, vascular complications, and organ dysfunction, humoral factors having various physiological functions such as adipokines have attracted attention. Humoral factors are produced in various peripheral organs besides the adipose tissue, and these peripheral organs closely cooperate via the humoral factors to maintain homeostasis in vivo, and on the other hand, a failure in the balance of the humoral factors is thought to contribute to arteriosclerosis and organ dysfunction. The present inventors have noted adrenomedullin (AM) and its receptor activity modifying protein (RAMP) system as one of such humoral factors.
Adrenomedullin (AM) is a peptide produced in the blood vessels and tissues of the whole body. It has become clear that AM has a variety of physiological functions including vasodilation function, fluid volume regulating function, hormone section regulation function, antioxidant function, antiinflammatory function and the like. The present inventors have thus far noted increased blood pressure in heterozygous AM knockout mice, and the aggravation of cardiac hypertrophy, fibrosis, nephropathy and arteriosclerosis, whereas AM-overexpressing mice were, on the contrary, recognized to have lower blood pressure and showed resistance to organ damages and arteriosclerosis; and thus reported that AM has an organ protective function, and antiarteriosclerotic function (refer to Non-Patent Documents 1 to 3).
Further, the present inventors were the first to clarify that AM is an essential molecule for blood vessel maturation and to stabilize the structure of blood vessels, through the observation that AM knockout mice were lethal at mid-gestation with severe hemorrhage and edema due to insufficient vascular development (refer to Non Patent Document 4). Moreover, it was recently reported that the AM concentration in blood elevates along with obesity and is correlated with the body mass index, and AM is expressed in adipose tissue, and this expression is upregulated with obesity conditions (refer to Non-Patent Documents 5 and 6). On the other hand, in AM knockout mice, with aging, along with obesity, glucose tolerance disorders and the aggravation of in vivo oxidative stress, the development of organ dysfunction was observed, suggesting a relationship between AM and metabolic syndrome.
[Non-Patent Document 1] T. Shindo et al., Circulation, 2000
[Non-Patent Document 2] Y. Imai, T. Sindo, et al., ATVB 2002
[Non-Patent Document 3] P. Niu, T. Shindo, et al., Circulation 2004
[Non-Patent Document 4] T. Shindo et al., Circulation 2001
[Non-Patent Document 5] J. Kato et al., Hypertens. Res. 2002
[Non-Patent Document 6] T. Nambu et al., Regul Pept. 2005